Abnormal　amyloid　beta　(Aβ)　aggregation　is　a　key　factor　in　Alzheimer’s　disease　(AD)　pathology.　Despite　efforts　to　develop　Aβ　aggregation　inhibitors,　efficient　screening　strategies　remain　limited.　Here,　we　initially　applied　structure-based　virtual　screening　to　target　Aβ　fibril　ends,　aiming　to　identify　compounds　that　could　effectively　combat　AD　neurodegeneration.　Using　this　approach,　we　screened　a　traditional　Chinese　medicine　library　with　thousands　of　compounds,　and　selected　high-scoring　hits　likely　to　inhibit　fibril　elongation　or　promote　fibril　depolymerization.　Forsythoside　A　emerged　as　the　most　potent　inhibitor,　effectively　reducing　Aβ40　aggregation　and　disassembling　pre-formed　fibrils,　as　confirmed　through　biophysical　assays　and　surface　plasmon　resonance　analysis.　Chemical　kinetics　further　elucidated　its　inhibitory　mechanism.　In　Caenorhabditis　elegans,　forsythoside　A　alleviated　Aβ-induced　toxicity　and　extended　the　lifespan　of　the　AD　transgenic　models.　Further　virtual　screening　and　experimental　validation　using　a　CNS-penetrant　compound　library　confirmed　the　robustness　of　our　strategy.　Our　study　underscores　the　effectiveness　of　virtual　screening　in　the　identification　of　Aβ　aggregation　inhibitors　and　emphasizes　the　critical　significance　of　targeting　fibril　ends.　(Figure　presented.)　©　The　Author(s)　2025.